ST6Gal-1 Sialyltransferase in Inflammation

ST6Gal-1 唾液酸转移酶在炎症中的作用

基本信息

批准号：
10159705
负责人：
Joseph TY Lau
金额：
$ 18.36万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159705
关键词：
2019-nCoV ABO blood group system Acute Address Algorithms Antibodies Antigens Attention Attenuated Autoimmune Process Automobile Driving B-Lymphocytes Blood Blood Platelets COVID-19 Cell Maturation Cell Survival Cell surface Chondroitin Sulfate A Chronic Coronavirus Data Deterioration Disease Disease Progression Enzymes Epitopes Extracellular Matrix Functional disorder Funding Future Granulopoiesis Immune Immune response Immunity Immunoglobulin G Immunoglobulin M Individual Inflammation Inflammatory Intravenous Life Malignant Neoplasms Mass Spectrum Analysis Middle East Respiratory Syndrome Coronavirus Modality Mus National Institute of Allergy and Infectious Disease Outcome Parents Pathogenesis Pathologic Patient-Focused Outcomes Patients Plasma Plasmapheresis Polysaccharides Production Property Publishing Recombinants Reporting Resources Risk Severity of illness Sialic Acids Sialyltransferases Structure Symptoms Syndrome System Testing Therapeutic Thrombosis Time Tn antigen Viral Work airway inflammation base blood group cytokine effective therapy glycosylation healthy volunteer inflammatory marker insight macrophage mimetics mortality novel therapeutics organ transplant rejection pandemic disease prognostic value response transmission process tumor volunteer

项目摘要

Project Summary (Supplement) COVID-19 is a pandemic in which the high mortality rate is driven by high infectivity and rampant transmission of the causative corona virus, SARS-CoV-2. The unpredictable and very rapid life-threatening deterioration in some but not all viral-positive patients remains unsolved and requires immediate attention. Plasmapheresis, used to treat patients with acute organ transplant rejection, ameliorates the severe symptoms of COVID-19 patients, suggesting a similar immune-related dysfunction in COVID-19. Emerging studies implicate altered glycans and glycosylation as central but overlooked contributors in COVID-19 pathogenesis. Among these studies: 1) Blood group A patients have significantly worse outcomes than blood group O; 2) the SARS-CoV-2 displays unique glycan structures, the TF and Tn antigens that are normally only expressed in cancer; 3) engaging host sialic acid glyan epitopes to facilitate viral entry and dispersal is well document in related corona viruses although not yet reported for SARS-CoV-2. Our preliminary data supports a glycosylation-axis in COVID-19 pathogenesis. Comparing 10 viral-positive patients with 10 healthy volunteers, we showed patient plasma have 1) IgGs and IgMs directed again a number of prominent cell surface glycan structures, including against TF and Tn antigens; and 2) a striking shift of anti- ABO from predominantly IgG to IgM (p<0.001 with just 10 patients and 10 volunteers). Additional observations, part of the ongoing parent NIAID-funded R01, identified a blood-borne glycan-modifying enzyme, ST6GAL1 with pleiotropic functions in promoting Ig production, B cell maturation, facilitating transitional B cell survival during selection, while attenuating inflammation by muting cytokine release from airway macrophages. We have also reported that platelets as critical contributors to ST6GAL1 function, natural circulating ST6GAL1 levels fluctuate depending on disease status, and that inoculation of recombinant ST6GAL1 mitigated acute airway inflammation in mice. We propose using an increase number of patient and healthy donor plasma to expand upon the unique anti- glycan antibodies and correlate with disease status. We will also address how glycosylation abnormalities drive plate dysfunction in COVID19 by assessing the ability of patient anti-glycan antibodies to activate platelets. These Aims should yield definitive insights into blood glycans in COVID-19. Future directions will test the utility of glycans, glycan-mimetics, and/or recombinant glycan-modifying enzymes such as ST6GAL1 as therapeutic modalities for COVID-19.

项目概要（补充） COVID-19 是一种大流行病，其高传染性和猖獗的传播导致了高死亡率致病冠状病毒 SARS-CoV-2。不可预测且非常迅速的危及生命的恶化一些但并非所有病毒阳性患者的问题仍未得到解决，需要立即关注。血浆置换术，用于治疗急性器官移植排斥反应患者，缓解COVID-19的严重症状患者，表明 COVID-19 中存在类似的免疫相关功能障碍。新兴研究表明改变聚糖和糖基化是 COVID-19 发病机制中的核心但被忽视的因素。其中研究：1）A 型血患者的预后明显比 O 型血患者差； 2) SARS-CoV-2 显示独特的聚糖结构，即通常仅在癌症中表达的 TF 和 Tn 抗原； 3）相关冠状病毒中充分记录了与宿主唾液酸聚糖表位结合以促进病毒进入和传播病毒，但尚未报道 SARS-CoV-2。我们的初步数据支持 COVID-19 发病机制中的糖基化轴。比较10个病毒阳性对 10 名健康志愿者的患者，我们显示患者血浆有 1) IgG 和 IgM，再次针对一些突出的细胞表面聚糖结构，包括针对 TF 和 Tn 抗原的聚糖； 2）反面的显着转变 ABO 从以 IgG 为主变为 IgM（仅 10 名患者和 10 名志愿者 p<0.001）。额外的观察， NIAID 资助的 R01 母体的一部分，鉴定出一种血源性聚糖修饰酶 ST6GAL1 促进 Ig 产生、B 细胞成熟、促进过渡期 B 细胞存活的多效性功能选择，同时通过抑制气道巨噬细胞释放细胞因子来减轻炎症。我们还有据报道，血小板是 ST6GAL1 功能的关键贡献者，自然循环 ST6GAL1 水平会波动取决于疾病状态，并且重组 ST6GAL1 的接种可减轻急性气道炎症在小鼠中。我们建议使用更多数量的患者和健康捐献者血浆来扩展独特的抗- 聚糖抗体并与疾病状态相关。我们还将讨论糖基化异常如何驱动通过评估患者抗聚糖抗体激活血小板的能力来评估 COVID19 中的血小板功能障碍。这些目标应该能够对 COVID-19 中的血聚糖产生明确的见解。未来的方向将测试实用性聚糖、聚糖模拟物和/或重组聚糖修饰酶（例如 ST6GAL1）作为治疗剂 COVID-19 的治疗方式。